Novel heterocycles 3

ABSTRACT

The invention relates to 7-(4-tert butyl-cyclohexyl)-imidazotriazinones, processes for their preparation and their use in medicaments, esp. for the treatment and/or prophylaxis of inflammatory processes and/or immune diseases.

The invention relates to 7-(4-tert butyl-cyclohexyl)-imidazotriazinones,processes for their preparation and their use in medicaments, esp. forthe treatment and/or prophylaxis of inflammatory processes and/or immunediseases.

Phosphodiesterases (PDEs) are a family of enzymes responsible for themetabolism of the intracellular second messengers cAMP (cyclic adenosinemonophosphate) and cGMP (cyclic guanosine monophosphate). PDE 4, as acAMP specific PDE, catalyses the conversion of cAMP to AMP and is themajor if not sole isoform of the phosphodiesterase enzymes present ininflammatory and immune cell types. Inhibition of this enzyme leads tothe accumulation of cAMP which, in these cells, leads to the inhibitionof a range of pro-inflammatory functions. Uncontrolled production ofinflammatory mediators can lead to acute and chronic inflammation,tissue damage, multi-organ failures and to death. Additionally,elevation of phagocyte cAMP leads to inhibition of oxygen radicalproduction. This cell function is more sensitive than others such asaggregation or enzyme release.

It is now recognised that both asthma and COPD (Chronic obstructivepulmonary disease) are chronic inflammatory lung diseases. In the caseof asthma the eosinophil is the predominant infiltrating cell.Subsequent release of superoxide radicals as well as damaging cationicproteins from these infiltrating cells are believed to play a role inthe progression of the disease and development of airwayhyperreactivity.

By contrast, in COPD the neutrophil is the predominant inflammatory celltype found in the lungs of sufferers. The action of mediators andproteases released in the environment of the lung is believed to resultin the irreversible airway obstruction seen in COPD. In particular theaction of proteases in degrading the lung matrix results in feweralveoli and is likely to be the major cause of accelerated long termlung function decline seen in this disease.

Treatment with a PDE 4 inhibitor is expected to reduce the inflammatorycell burden in the lung in both of these diseases [M. S. Barnette, “PDE4 inhibitors in asthma and chronic obstructive pulmonary disease”, in:Progress in Drug Research, Birkhäuser Verlag, Basel, 1999, pp. 193-229;H. J. Dyke and J. G. Montana, “The therapeutic potential of PDE 4inhibitors”, Exp. Opin. Invest. Drugs 8, 1301-1325 (1999)].

While PDE 4-inhibitors also usually produce side effects like vomiting,it has been shown that these side effects correlate with the affinity toa high affinity binding site for rolipram, and that emesis is reduced incompounds with a decreased affinity to this binding site (J. Med. Chem.1996, 39, 120-125).

WO 99/24433 and WO 99/67244 describe 2-phenyl-imidazotriazinones assynthetic intermediates for the synthesis of2-(aminosulfonyl-phenyl)-imidazotriazinones as inhibitors ofcGMP-metabolizing phosphodiesterases.

U.S. Pat. No. 4,278,673 discloses 2-aryl-imidazotriazinones with cAMPphosphodiesterase inhibitory activity for the treatment of i.a. asthma.

The present invention relates to compounds of the general formula (I)

in which

-   -   R¹ denotes (C₆-C₁₀)-aryl, which is optionally substituted by        identical or different residues selected from the group        consisting of halogen, (C₁-C₄)-alkyl, tri-fluoromethyl, cyano,        nitro und trifluoromethoxy, or        -   denotes (C₁-C₈)-alkyl, which is optionally substituted by 3-            to 10-membered carbocyclyl, or        -   denotes 3- to 10-membered carbocyclyl, which is optionally            substituted by identical or different (C₁-C₄)-alkyl            residues,    -   and    -   R² denotes 4-tert-butyl-cyclohex-1-yl,

Another embodiment of the invention relates to compounds of the generalformula (I), in which

-   -   R¹ denotes naphthyl, or        -   denotes phenyl, which is optionally substituted by identical            or different halogen atoms    -   and    -   R² has the meaning indicated above.

Another embodiment of the invention relates to compounds of the generalformula (I), in which R¹ has the meaning indicated above, and R² denotescis-4-tert-butyl-cyclohex-1-yl.

The compounds according to this invention can also be present in theform of their salts, hydrates and/or solvates.

In general, salts with organic or inorganic bases or acids may bementioned here.

Physiologically acceptable salts are preferred in the context of thepresent invention.

Physiologically acceptable salts can also be salts of the compoundsaccording to this invention with inorganic or organic acids. Preferredsalts are those with inorganic acids such as, for example, hydrochloricacid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts withorganic carboxylic or sulphonic acids such as, for example, acetic acid,maleic acid, fumaric acid, malic acid, citric acid, tartaric acid,ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid ornaphthalene-disulphonic acid. Preferred pyridinium salts are salts incombination with halogen.

The compounds according to this invention can exist in stereoisomericforms which either behave as image and mirror image (enantiomers), orwhich do not behave as image and mirror image (diastereomers). Theinvention relates both to the enantiomers and to the racemates, as wellas the pure diastereomer and mixtures thereof. The racemates, like thediastereomers, can be separated into the stereoisomerically uniformconstituents according to known methods.

Especially preferred are compounds of the general formula (I), whereinR¹ denotes 1-naphthyl or 3-halo-phenyl.

Hydrates of the compounds of the invention are stoichiometriccompositions of the compounds with water, such as for example hemi-,mono-, or dihydrates.

Solvates of the compounds of the invention or their salts arestoichiometric compositions of the compounds with solvents.

(C₁-C₈)-alkyl, and (C₁-C₄)-alkyl in general represent straight chain orbranched alkyl residues with 1 to 8, or 1 to 4 carbon atoms,respectively. The alkyl residues can be saturated or partiallyunsaturated, i.e. contain one or more double and/or triple bonds.Saturated alkyl residues are preferred. The following alkyl residues arementioned by way of example: methyl, ethyl, n-propyl, isopropyl, allyl,propargyl, tert.butyl, pentyl, hexyl, heptyl, and octyl,

(C₆-C₁₀)-Aryl in general represents an aromatic residue with 6 to 10carbon atoms. Phenyl and naphthyl are preferred.

3- to 10-membered carbocyclyl in general represents a mono- orpolycyclic, carbocyclic residue with 3 to 10 ring atoms. 3- to8-membered carbocyclyl is preferred. Mono- and bicyclic carbocyclylresidues are preferred. Especially preferred are monocyclic carbocyclylresidues. The carbocyclyl residues can be saturated or partiallyunsaturated. Saturated carbocyclyl residues are preferred. Especiallypreferred are (C₃-C₁₀)-cycloalkyl and (C₄-C₇)-cycloalkyl residues. Thefollowing carbocyclyl residues are mentioned by way of example:cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cycloheptyl, norborn-1-yl, norborn-2-yl, norborn-7-yl,norborn-2-en-7-yl, cyclooctyl, cubyl, cyclononyl, cyclodecyl, decalinyl,adamant-1-yl, adamant-2-yl.

Halogen in general represents fluoro, chloro, bromo and iodo. Fluoro,chloro, and bromo are preferred. Fluoro, and chloro are especiallypreferred.

Unless specified otherwise, when groups in compounds of the inventionare optionally substituted, substitution by up to three identical ordifferent residues is generally preferred.

The invention furthermore provides a process for preparing the compoundsof the general formula (I) according to the invention, characterized inthat

-   -   compounds of the general formula (II)        in which    -   R² is as defined above    -   and    -   L represents straight-chain or branched alkyl having up to 4        carbon atoms, are condensed with compounds of the general        formula (III)        in which    -   R¹ is as defined above,    -   preferably using ethanol as a solvent, to the compounds of the        general formula (IV),        in which R¹ and R² are as defined above,    -   which can optionally after isolation be reacted with a        dehydrating agent, preferably phosphorus oxytrichloride, to        yield the compounds of the general formula (I).

The compounds of the general formula (IV) can alternatively be preparedby

-   -   [A] condensation of compounds of the general formula (IIa),        in which    -   L is as defined above,    -   with compounds of the general formula (III) to compounds of the        general formula (IVa),        in which    -   R¹ is as defined above,    -   preferably using ethanol as a solvent,    -   [B] followed by hydrolysis of the compounds of the general        formula (IVa) to compounds of the general formula (V),        in which    -   R¹ is as defined above,    -   [C] and finally by condensation of the compounds of the general        formula (V) with compounds of the general formula (VI),        in which    -   R² is as defined above, and    -   T represents a leaving group, preferably chlorine.

The process according to the invention can be illustrated using thefollowing scheme as an example:

Solvents which are suitable for the individual steps are the customaryorganic solvents which do not change under the reaction conditions.These preferably include ethers, such as diethyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such asbenzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions,or halogenated hydrocarbons, such as dichloromethane, trichloromethane,carbon tetrachloride, dichloroethane, trichloroethylene orchlorobenzene, or ethyl acetate, dimethylformamide, hexamethylphosphorictriamide, acetonitrile, acetone, dimethoxyethane or pyridine. It is alsopossible to use mixtures of the above-mentioned solvents. Particularpreference is given to ethanol for the reaction II/IIa+III→IV/IVa anddichloroethane for the cyclisation IV→I.

The reaction temperature can generally be varied within a relativelywide range. In general, the reaction is carried out in a range of from−20° C. to 200° C., preferably of from 0° C. to 100° C.

The process steps according to the invention are generally carried outunder atmospheric pressure. However, it is also possible to operateunder superatmospheric pressure or under reduced pressure (for example,in a range of from 0.5 to 5 bar).

The compounds of the general formula (IVa) are preferably hydrolysed tocompounds of the general formula (V) under acidic conditions as forexample in refluxing 2N hydrochloric acid.

The compounds of the general formula (V) are condensed with thecompounds of the general formula (VI) to compounds of the generalformula (IV) in inert solvents, if appropriate in the presence of abase.

Suitable inert solvents are the customary organic solvents which do notchange under the reaction conditions. These preferably include ethers,such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether,or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexaneor mineral oil fractions, or halogenated hydro-carbons, such asdichloromethane, trichloromethane, carbon tetrachloride,dichloro-ethylene, trichloroethylene or chlorobenzene, or ethyl acetate,dimethylformamide, hexamethylphosphoric triamide, acetonitrile, acetone,dimethoxyethane or pyridine. It is also possible to use mixtures of theabovementioned solvents.

Suitable bases are generally alkali metal hydrides or alkali metalalkoxides, such as, for example, sodium hydride or potassiumtert-butoxide, or cyclic amines, such as, for example, piperidine,pyridine, dimethylaminopyridine or (C₁-C₄)-alkylamines, such as, forexample, triethylamine. Preference is given to triethylamine, pyridineand/or dimethylaminopyridine.

The base is generally employed in an amount of from 1 mol to 4 mol,preferably from 1.2 mol to 3 mol, in each case based on 1 mol of thecompound of the formula (V).

The reaction temperature can generally be varied within a relativelywide range. In general, the reaction is carried out in a range of from−20° C. to 200° C., preferably of from 0° C. to 100° C.

Some of the compounds of the general formula (II) are known, or they arenovel, and they can then be prepared by

-   -   converting compounds of the general formula (VI)        R²—CO-T   (VI)        in which    -   R² is as defined above    -   and    -   T represents halogen, preferably chlorine,    -   initially by reaction with a-amino-butyric acid in inert        solvents, if appropriate in the presence of a base and        trimethylsilyl chloride, into the compounds of the general        formula (VII),        in which    -   R² is as defined above,    -   and finally reacting with the compound of the formula (VIII)        in which    -   L is as defined above,    -   in inert solvents, if appropriate in the presence of a base.

The compounds of the general formula (IIa) can be prepared analogously.

Suitable solvents for the individual steps of the process are thecustomary organic solvents which do not change under the reactionconditions. These preferably include ethers, such as diethyl ether,dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, suchas benzene, toluene, xylene, hexane, cyclohexane or mineral oilfractions, or halogenated hydrocarbons, such as dichloromethane,trichloromethane, carbon tetrachloride, dichloroethylene,trichloroethylene or chlorobenzene, or ethyl acetate, dimethylformamide,hexamethylphosphoric triamide, acetonitrile, acetone, dimethoxyethane orpyridine. It is also possible to use mixtures of the above-mentionedsolvents. Particular preference is given to dichloromethane for thefirst step and to a mixture of tetrahydrofuran and pyridine for thesecond step.

Suitable bases are generally alkali metal hydrides or alkali metalalkoxides, such as, for example, sodium hydride or potassiumtert-butoxide, or cyclic amines, such as, for example, piperidine,pyridine, dimethylaminopyridine or (C₁-C₄)-alkylamines, such as, forexample, triethylamine. Preference is given to triethylamine, pyridineand/or dimethylaminopyridine.

The base is generally employed in an amount of from 1 mol to 4 mol,preferably from 1.2 mol to 3 mol, in each case based on 1 mol of thecompound of the formula (V).

The reaction temperature can generally be varied within a relativelywide range. In general, the reaction is carried out in a range of from−20° C. to 200° C., preferably of from 0° C. to 100° C.

The compounds of the general formulae (VI) and (VII) are known per se,or they can be prepared by customary methods.

The compounds of the general formula (III) are known or can be preparedby

-   -   reacting compounds of the general formula (IX)        R¹—Y   (IX)        in which    -   R¹ is as defined above, and    -   Y represents a cyano, carboxyl, methoxycarbonyl or        ethoxycarbonyl group,    -   with ammonium chloride in toluene and in the presence of        trimethylaluminium in hexane in a temperature range of from        −20° C. to room temperature, preferably at 0° C. and atmospheric        pressure, and reacting the resulting amidine, if appropriate in        situ, with hydrazine hydrate.

The compounds of the general formula (IX) are known per se, or they canbe prepared by customary methods.

The compounds of the general formula (I) inhibit the PDE 4 resident inthe membranes of human neutrophils and display an especially favourablebinding profile versus the PDE 4 high affinity site, binding to which ismade responsible for side effects like emesis. One measured functionalconsequence of this inhibition was inhibition of superoxide anionproduction by stimulated human neutrophils.

The compounds of the general formula (I) can therefore be employed inmedicaments for the treatment of inflammatory processes, esp. acute andchronic inflammatory processes, and/or immune diseases.

The compounds according to the invention are preferably suitable for thetreatment and prevention of inflammatory processes, i.e. acute andchronic inflammatory processes, and/or immune diseases, such asemphysema, alveolitis, shock lung, all kinds of chronic obstructivepulmonary diseases (COPD), adult respiratory distress syndrome (ARDS),asthma, bronchitis, cystic fibrosis, eosinophilic granuloma,arteriosclerosis, arthrosis, inflammation of the gastro-intestinaltract, myocarditis, bone resorption diseases, reperfusion injury,Crohn's disease, ulcerative colitis, systemic lupus erythematosus, typeI diabetes mellitus, psoriasis, anaphylactoid purpura nephritis, chronicglomerulonephritis, inflammatory bowel disease, atopic dermatitis, otherbenign and malignant proliferative skin diseases, allergic rhinitis,allergic conjunctivitis, vernal conjunctivitis, arterial restenosis,sepsis and septic shock, toxic shock syndrome, grafts vs. host reaction,allograft rejection, treatment of cytokine-mediated chronic tissuedegeneration, rheumatoid arthritis, arthritis, rheumatoid spondylitis,osteoarthritis, coronary insufficiency, myalgias, multiple sclerosis,malaria, AIDS, cachexia, prevention of tumor growth and tissue invasion,leukemia, depression, memory impairment and acute stroke. The compoundsaccording to the invention are additionally suitable for reducing thedamage to infarct tissue after reoxygenation.

The compounds of formula (I) according to the invention can be used asactive compound components for the production of medicaments. For this,they can be converted into the customary formulations such as tablets,coated tablets, aerosols, pills, granules, syrups, emulsions,suspensions and solutions in a known manner using inert, non-toxic,pharmaceutically suitable excipients or solvents. Preferably, thecompounds according to the invention are used here in an amount suchthat their concentration in the total mixture is approximately 0.5 toapproximately 90% by weight, the concentration, inter alia, beingdependent on the corresponding indication of the medicament.

The above-mentioned formulations are produced, for example, by extendingthe active compounds with solvents and/or excipients having the aboveproperties, where, if appropriate, additionally emulsifiers ordispersants and, in the case of water as the solvent, alternatively anorganic solvent, have to be added.

Administration is carried out in a customary manner, preferably orally,transdermally or parenterally, for example perlingually, buccally,intravenously, nasally, rectally or inhalationally.

For human use, in the case of oral administration, it is recommendableto administer doses of from 0.001 to 50 mg/kg, preferably of 0.01mg/kg-20 mg/kg. In the case of parenteral administration, such as, forexample, intravenously or via mucous membranes nasally, buccally orinhalationally, it is recommendable to use doses of 0.001 mg/kg-0.5mg/kg.

In spite of this, if appropriate, it may be necessary to depart from theamounts mentioned above, namely depending on the body weight or the typeof administration route, on the individual response towards themedicament, the manner of its formulation and the time or interval atwhich administration takes place. Thus, in some cases it may besufficient to manage with less than the above mentioned minimum amount,while in other cases the upper limit mentioned must be exceeded. In thecase of the administration of relatively large amounts, it may berecommendable to divide these into several individual doses over thecourse of the day.

Test Descriptions

1. Preparation of Human PMN

Human PMN (polymorphonuclear neutrophil leucocytes) are readily purifiedfrom peripheral blood. Phosphodiesterase in these cells is predominantlylocated in the membrane fraction. Inhibitory potency of compoundsagainst this preparation correlate well with the anti-inflammatoryactivity as measured by inhibition of superoxide production.

Blood was taken from healthy subjects by venous puncture and neutrophilswere purified by dextran sedimentation and density gradientcentrifugation on Ficoll Histopaque and resuspended in the bufferedmedium.

2. Assay of Human PMN Phosphodiesterase

This was performed as a particulate fraction from human PMN essentiallyas described by Souness and Scott [Biochem. J. 291, 389-395 (1993)].Particulate fractions were treated with sodium vanadate/glutathione asdescribed by the authors to express the descrete stereospecific site onthe phosphodiesterase enzyme. The prototypical PDE 4 inhibitor,rolipram, had an IC₅₀ value in the range 450 nM-1500 nM, thus definingthis preparation as the so-called “low affinity” [L] form. Thepreparation examples had IC₅₀ values within the range of 0.1 nM-10,000nM.

3. Inhibition of FMLP-Stimulated Production of Superoxide Radical Anions

Neutrophils (2.5×10⁵ m⁻¹) were mixed with cytochrome C (1.2 mg/ml) inthe wells of a microtitre plate. Compounds according to the inventionwere added in dimethyl sulphoxide (DMSO). Compound concentration rangedfrom 2.5 nM to 10 μM, the DMSO concentration was 0.1% v/v in all wells.After addition of cytochalasin b (5 μg×ml⁻¹) the plate was incubated for5 min at 37° C. Neutrophils were then stimulated by addition of 4×10⁻⁸ MFMLP (N-Formyl-Met-Leu-Phe) and superoxide generation measured assuperoxide dismutase inhibitable reduction of cytochrome C by monitoringthe OD₅₅₀ in a Thermomax microtitre plate spectrophotometer. Initialrates were calculated using a Softmax kinetic calculation programme.Blank wells contained 200 units of superoxide dismutase.

The inhibition of superoxide production was calculated as follows:$\frac{\left\lbrack {1 - \left( {{Rx} - {Rb}} \right)} \right\rbrack}{\left( {{Ro} - {Rb}} \right)} \times 100$

-   -   Rx=Rate of the well containing the compound according to the        invention    -   Ro=Rate in the control well    -   Rb=Rate in the superoxide dismutase containing blank well

The preparation examples had IC₅₀ values within the range of 0.1nM-10,000 nM.

4. Assay of Binding to the Rolipram Binding Site (PDE 4 High AffinitySite; “H-PDE 4 Form”) in Rat Brain Membranes

The activity of compounds on the PDE 4 high affinity site (“H-PDE 4form”) is readily measured by determining their potency for displacementof [³H]-rolipram from its binding site in rat brain membranes. Activityat this site is believed to be a measure of side effect potential (e.g.stimulation of stomach acid secretion, nausea and emesis).

The rolipram binding site assay was performed essentially as describedby Schneider et al. [Eur. J. Pharmacol. 127, 105-115 (1986)].

5. Lipopolysaccharide (LPS)—Induced Neutrophil Influx Into Rat Lung

Intranasal administration of LPS to rats causes a marked influx ofneutrophils into the lungs measurable by histological or biochemical(myeloperoxidase content of the cell pellet) analysis of thebronchoalveolar lavage fluid 24 h later. Rats were treated with testcompound or vehicle administered by the oral route 1 h prior to and 6 hafter administration of intranasal LPS. 24 hours later animals wereeuthanatized and their lungs lavaged with PBS (phosphate bufferedsaline). Neutrophil and total cell numbers were analysed.

6. Emetic Potential in the Marmoset

Vehicle or test compound was administered by the oral route to consciousmarmosets. Animals were observed for emetic episodes or abnormalbehaviour for 1 h post dosing. In some experiments, if no adverseresponse was seen, a separate group of animals was tested at ½ log dosehigher until emesis or abnormal behaviour was observed. The highest doseat which no abnormal behavior or emetic episodes occurred was recordedas the NOEL.

Materials and Methods LC-MS method A: LC-parameters solution Aacetonitrile solution B 0.3 g 30% HCl/1 water column oven 50° C.; columnSymmetry C18 2.1 × 150 mm gradient: time [min] % A % B flow [ml/min] 010 90 0.9 3 90 10 1.2 6 90 10 1.2 LC-MS method B: LC-parameters solutionA acetonitrile/0.1% formic acid solution B water/0.1% formic acid columnoven 40° C.; column Symmetry C18 2.1 × 50 mm gradient: time [min] % A %B flow [ml/min] 0 10 90 0.5 4 90 10 0.5 6 90 10 0.5 6.1 10 90 1.0 7.5 1090 0.5

GC-MS method A: Column: HP-5 30 m × 320 μm × 0.25 μm Carrier Gas: HeliumMode: Constant flow, initial flow: 1.5 ml/min Oven ramp: initial temp:60° C. irntial time: 1 min rate: 14° C./min up to 300° C., then 300° C.2 min

Unless specified otherwise, the following chromatographic conditionswere applied: chromatography was performed on silica gel Si 60; forflash chromatography, the usual conditions were followed as described inStill, J. Org. Chem. 43, 2923 (1978); mixtures of dichloromethane andmethanol or cyclohexane and ethylacetate were used as eluants. Unlessspecified otherwise, reactions were executed under an argon atmosphereand under anhydrous conditions.

Abbreviations:

HPLC=high performance liquid chromatography

MS=mass spectroscopy

NMR=nuclear magnetic resonance spectroscopy

LC-MS=liquid chromatography combined with mass spectroscopy

GC-MS=gas chromatography combined with mass spectroscopy

MeOH=methanol

DMF=N,N-dimethylformamide

DMSO=dimethylsulfoxide

Starting Materials

EXAMPLE 1A 2-(Acetylamino)butanoic acid

163 g (1.58 mol) 2-aminobutanoic acid are dissolved in acetic acid, and242 g (2.37 mol) acetic anhydride are added dropwise. The mixture isstirred for 2 h at 100° C. until completion of reaction, then thesolution evaporated to dryness in vacuo. The solid residue is suspendedin ethyl acetate, filtered and washed with diethyl ether.

Yield: 220 g (96%) ¹H-NMR (Methanol-d4): δ=0.97 (t, 3 H), 1.65-1.93 (m,2 H), 1.99 (s, 3 H), 4.29 (q, 1 H) ppm.

EXAMPLE 2A Ethyl 3-(acetylamino)-2-oxopentanoate

9.2 g (63.4 mmol) 2-(Acetylamino)butanoic acid are suspended in 120 mltetra-hydrofurane and heated to reflux together with 15.0 g (190 mmol)pyridine and a bit of N,N-dimethylaminopyridine. While heating atreflux, 17.3 g (127 mmol) ethyl chloro(oxo)acetate are added dropwise.The reaction mixture is heated at reflux until no more evolution of gascan be observed. After cooling down to room temperature, the reactionmixture is added to ice water and the organic phase extracted with ethylacetate. The dried organic phase is evaporated to dryness in vacuo,dissolved in ethanol and the solution directly used for the nextreaction.

EXAMPLE 3A 3-Bromobenzenecarboximidamide hydrochloride

1.18 g (22 mmol, 2 equiv.) ammonium chloride are suspended in 40 ml ofdry toluene under an argon atmosphere, and the mixture is cooled to 0°C. 1 ml (22 mmol, 2 equiv.) of a 2M solution of trimethylaluminium inhexane are added dropwise, and the reaction mixture is stirred at roomtemperature until no more evolution of gas is observed. After additionof 2.0 g (11 mmol, 1 equiv.) 3-bromo-benzonitrile, the mixture isstirred at 80° C. bath temperature over night. It is then cooled down to0° C. and 50 ml of methanol are added with subsequent stirring of 1 hourat room temperature. After filtration, the solid is washed with methanolfor several times, the solution is evaporated to dryness in vacuo andthe residue washed with methanol.

Yield: 2.02 g (78%) ¹H-NMR (DMSO-d₆, 300 MHz): δ=7.6 (m, 1H), 7.8 (m,1H), 8.0 (m, 1H), 8.1 (s, 1H) ppm.

EXAMPLE 4A 4-Fluorobenzenecarboximidamide hydrochloride

In analogy to the procedure for Example 3A, 2.0 g (16.5 mmol)4-fluorobenzonitrile and proportionate amounts of the other reagents areused.

Yield: 2.9 g (100%) ¹H-NMR (DMSO-d₆, 200 MHz): δ=7.5 (m, 2H), 8.0 (m,2H) ppm.

EXAMPLE 5A Cyclopropanecarboximidamide Hydrochloride

In analogy to the procedure for Example 3A, 6.71 g (100 mmol)cyclopropanecarbo-nitrile and proportionate amounts of the otherreagents are used.

Yield: 7.3 g (61%) GC/MS (method A): retention time 3.42 min., m/z 85.1[M+H]⁺

EXAMPLE 6A Cyclopentanecarboximidamide Hydrochloride

In analogy to the procedure for Example 3A, 7.51 g (79.0 mmol)cyclopentane-carbonitrile and proportionate amounts of the otherreagents are used.

Yield: 3.9 g (33%) LC-MS (method A): retention time 0.42 min., m/z 113[M+H]⁺

EXAMPLE 7A 2,2-Dimethylpropaneimidamide hydrochloride

In analogy to the procedure for Example 3A, 8.31 g (100 mmol)pivalonitrile and proportionate amounts of the other reagents are used.The crude product is used in the next step without further purification.

Yield: 6 g crude product

EXAMPLE 8A 3-Nitrobenzenecarboximidamide hydrochloride

In analogy to the procedure for Example 3A, 30.0 g (203 mmol)3-nitrobenzonitrile and proportionate amounts of the other reagents areused.

Yield: 24.5 g (47%) LC-MS (method A): retention time 0.40 min., m/z 166[M+H]⁺

EXAMPLE 9A 1-Naphthalenecarboximidamide hydrochloride

14 g (261 mmol, 2 equiv.) ammonium chloride are suspended in 150 ml ofdry toluene under an argon atmosphere, and the mixture is cooled to 0°C. 130 ml (260 mmol, 2 equiv.) of a 2M solution of trimethylaluminium inhexane are added dropwise, and the reaction mixture is stirred at roomtemperature until no more evolution of gas is observed. After additionof 20 g (130 mmol, 1 equiv.) 1-cyano-naphthalene, the mixture is stirredat 80° C. bath temperature over night. The mixture is cooled and pouredinto a slurry of silica in methylene chloride. After filtration, thesolid is washed with methanol for several times, the solution isevaporated to dryness in vacuo and the residue washed with methanol. Thecombined filtrates are pooled and stirred in a mixture of methylenechloride containing 10% methanol.

Yield: 9.88 g (37%) ¹H-NMR (DMSO-d₆, 300 MHz): δ=7.6-7.8 (m, 4H), 8.0(d, 1H), 8.1 (m, 1H), 8.2 (d, 1H) ppm, 9.5 (br s, 4H) ppm.

EXAMPLE 10AN-{1-[3-(3-Bromophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

2.02 (8.6 mmol, 1 equiv.) 3-bromobenzenecarboximidamide hydrochlorideare suspended in 50 ml of ethanol and 1.47 g (10.2 mmol, 1,2 equiv.)hydrazine hydrate are added. After stirring at room temperature for 1hour, 2.59 g (13 mmol, 1.5 equiv) of the compound of Example 2A,dissolved in 10 ml of ethanol, are added. The reaction mixture isstirred at 80° C. (bath temperature) for 4 hours and then at roomtemperature over night. The mixture is evaporated to dryness in vacuoand the product is purified by chromatography (flash or columnchromatography or preparative HPLC).

Yield: 758 mg (25%) ¹H-NMR (DMSO-d₆, 200 MHz): δ=0.9 (t, 3H), 1.6 (m,1H), 1.8 (m, 1H), 1.9 (s, 3H), 4.9 (m, 1H), 7.5 (m, 1H), 7.8 (m, 1H),8.0 (m, 1H), 8.2 (m, 2H), 14.1 (br. s, 1H) ppm.

EXAMPLE 11AN-{1-[3-(4-Fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 10A, 2.0 g (11.4 mmol)4-fluorobenzene-carboximidamide hydrochloride and proportionate amountsof the other reagents are used.

Yield: 1.47 g (44%) ¹H-NMR (DMSO-d₆, 300 MHz): δ=0.9 (t, 3H), 1.6 (m,1H), 1.8 (m, 1H), 1.9 (s, 3H), 4.9 (m, 1H), 7.5 (m, 2H), 8.1 (m, 3H),14.1 (br. s, 1H) ppm.

EXAMPLE 12AN-{1-[3-(3-Fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 10A, 2.0 g (11.4 mmol)3-fluorobenzene-carboximidamide hydrochloride and proportionate amountsof the other reagents are used.

Yield: 781 mg (23%) ¹H-NMR (DMSO-d₆, 300 MHz): δ=0.9 (t, 3H), 1.6 (m,1H), 1.8 (m, 1H), 1.9 (s, 3H), 4.9 (m, 1H), 7.5 (m, 1H), 7.7 (m, 1H),7.8 (m, 1H), 7.9 (m, 1H), 8.2 14.1 (br. s, 1H) ppm.

EXAMPLE 13AN-{1-[3-(3-Chlorophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 10A, 1.5 g (7.9 mmol)3-chlorobenzene-carboximidamide hydrochloride and proportionate amountsof the other reagents are used.

Yield: 441 mg (18%) ¹H-NMR (DMSO-d₆, 300 MHz): δ=0.9 (t, 3H), 1.6 (m,1H), 1.8 (m, 1H), 1.9 (s, 3H), 4.9 (m, 1H), 7.6 (m, 1H), 7.7 (m, 1H),8.0 (m, 1H), 8.1 (m, 1H), 8.2 (d, 1H), 14.1 (br. s, 1H) ppm.

EXAMPLE 14AN-{1-[3-(2-Bromophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 10A, 1.64 g (7.0 mmol)2-bromobenzene-carboximidamide hydrochloride and proportionate amountsof the other reagents are used.

Yield: 1.0 g (41%) LC/MS (B): MS (ES+): 351 (M+H⁺), retention time 2.34min.

EXAMPLE 15AN-[1-(3-Cyclohexyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]acetamide

In analogy to the procedure for Example 10A, 1.50 g (9.2 mmol)cyclohexane-carboximidamide hydrochloride and proportionate amounts ofthe other reagents are used.

Yield: 1.17 g (46%) ¹H-NMR (DMSO-d₆, 200 MHz): δ=0.9 (t, 3H), 1,2 (m,3H), 1.5 (m, 3H), 1.8 (m, 4H), 1.9 (s, 3H), 2.5 (m, 1H), 4.8 (m, 1H),8.1 (d, 1H), 13.4 (br.s, 1H) ppm.

EXAMPLE 16AN-{1-[3-(4-Bromophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 10A, 10.2 g (43.3 mmol)4-bromobenzene-carboximidamide hydrochloride and proportionate amountsof the other reagents are used.

Yield: 5.23 g (34%) ^(H-NMR ()400 MHz, CD₃OD): δ=1.01 (t, 3 H),1.66-1.79 (m, 1 H), 1.91-2.06 (m, 4 H, s at 1.99), 5.02-5.09 (m, 1 H),7.75 (d, 2 H), 7.93 (d, 2 H) ppm.

EXAMPLE 17AN-[1-(3-Cyclopropyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]acetamide

In analogy to the procedure for Example 10A, 7.30 g (60.5 mmol)cyclopropane-carboximidamide hydrochloride and proportionate amounts ofthe other reagents are used. The crude product is used in the next stepwithout further purification.

Yield: 4.9 g (34%) crude material

EXAMPLE 18AN-[1-(3-Cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]acetamide

In analogy to the procedure for Example 10A, 3.50 g (23.6 mmol)cyclopentane-carboximidamide hydrochloride and proportionate amounts ofthe other reagents are used.

Yield: 1.7 g (27%) LC/MS (method A): retention time 1.60 min., m/z 265[M+H]⁺

EXAMPLE 19AN-[1-(3-tert-Butyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]acetamide

In analogy to the procedure for Example 10A, 6.0 g (11.0 mmol)2,2-dimethylpro-paneimidamide hydrochloride and proportionate amounts ofthe other reagents are used.

Yield: 1.77 g (64%) LC/MS (method A): retention time 1.59 min., m/z 253[M+H]⁺

EXAMPLE 20AN-{1-[3-(3-Nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 10A, 35.0 g (174 mmol)3-nitrobenzene-carboximidamide hydrochloride and proportionate amountsof the other reagents are used.

Yield: 13.6 g (25%) ¹H-NMR (200 MHz, CDCl₃): δ=0.97 (t, 3 H), 1.83-2.08(m, 5 H, s at 2.02), 5.09 (m, 1 H), 7.76 (t, 1 H), 8.45 (d, 1H), 8.58(d, 1H), 9.12 (s, 1 H) ppm.

EXAMPLE 21AN-[1-(5-Oxo-3-phenyl-4,5-dihydro-1,2,4-triazin-6-yl)propyl]acetamide

In analogy to the procedure for Example 10A, 7.26 g (46.8 mmol)benzenecarbox-imidamide hydrochloride and proportionate amounts of theother reagents are used.

Yield: 10.1 g(80%) 1H-NMR (DMSO-d₆, 300 MHz): δ=0.9 (t, 3H), 1.5 (m,1H), 1.8 (m, 1H), 1.9 (s, 3H), 4.9 (m, 1H), 7.5 (m, 3H), 8.1 (m, 3H),14.1 (br. s, 1H) ppm.

EXAMPLE 22AN-{1-[3-(1-Naphthyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

1.0 g (4.84 mmol, 1 equiv.) 1-Naphthalenecarboximidamide hydrochlorideare suspended in 2 ml of DMSO and 0.29 g (5.81 mmol, 1,2 equiv.)hydrazine hydrate are added. After stirring at room temperature for 16hours, 1.45 g (7.3 mmol, 1.5 equiv.) of the compound of Example 2A,dissolved in 10 ml of ethanol, are added. The reaction mixture isstirred at reflux for 1 hour and then at 60° C. (bath temperature) for 4hours and then at room temperature over night. The mixture is evaporatedto dryness in vacuo and the product is purified by flash chromatography.

Yield: 7.1 g (70%) ¹H-NMR (DMSO-d₆, 300 MHz): δ=1.0 (t, 3H), 1.6-1.7 (m,2H), 1.9 (s, 3H), 5.0 (m, 1H), 7.5-8.2 (m, 8H), 14.0 (br. s, 1H) ppm.

EXAMPLE 23A 6-(1-Aminopropyl)-3-(3-bromophenyl)-1,2,4-triazin-5(4H)-one

749 mg (2.13 mmol) of Example 10A are heated to reflux in 20 ml 2 Nhydrochloric acid for 18 hours. After cooling down to room temperature,the mixture is neutralized with 10% NaOH and, after addition of ethanol,evaporated to dryness in vacuo. The residue is treated with methanol andthe filtrate separated from the salts. The filtrate is evaporated todryness in vacuo and the product purified by chromatography (flash orcolumn chromatography or preparative HPLC).

Yield: 320 mg (49%) 1H-NMR (DMSO-d₆, 200 MHz): δ=0.9 (t, 3H), 1.9 (m,2H), 4.3 (d/d, 1H), 7.4 (m, 1H), 7.6 (m, 1H), 8.1 (br. s, 2H), 8.2 (m,1H), 8.4 (m, 1H) ppm.

EXAMPLE 24A 6-(1-Aminopropyl)-3-(4-fluorophenyl)-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 23A, 1.46 g (5.0 mmol) ofExample 11A and proportionate amounts of the other reagents are used.

Yield: 970 mg (78%) LC/MS (A): MS (ESI): 249 (M+H⁺), retention time 0.50min

EXAMPLE 25A 6-(1-Aminopropyl)-3-(3-fluorophenyl)-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 23A, 1.1 g (3.8 mmol) of Example12A and proportionate amounts of the other reagents are used.

Yield: 594 mg (63%) LC/MS (A): MS (ESI): 249 (M+H⁺), retention time 0.49min

EXAMPLE 26A 6-(1-Aminopropyl)-3-(3-chlorophenyl)-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 23A, 419 mg (1.4 mmol) ofExample 13A and proportionate amounts of the other reagents are used.

Yield: 280 mg (77%) ¹H-NMR (DMSO-d₆, 300 MHz): δ=0.9 (t, 3H), 1.9 (m,1H), 2.0 (m, 1H), 4.3 (d/d, 1H), 7.5 (m, 2H), 8.2 (br. m, 4H) ppm.

EXAMPLE 27A 6-(1-Aminopropyl)-3-(2-bromophenyl)-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 23A, 1.00 g (2.85 mmol) ofExample 14A and proportionate amounts of the other reagents are used.

Yield: 152 mg (17%) ¹H-NMR (DMSO-d₆, 300 MHz): δ=0.9 (t, 3H), 1.9 (m,1H), 2.0 (m, 1H), 4.3 (d/d, 1H), 7.3 (m, 1H), 7.4 (m, 1H), 7.5 (m, 1H),7.7 (m, 1H) ppm.

EXAMPLE 28A 6-(1-Aminopropyl)-3-cyclohexyl-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 23A, 1.14 g (4.10 mmol) ofExample 15A and proportionate amounts of the other reagents are used.

Yield: 128 mg (13%) ¹H-NMR (DMSO-d₆, 300 MHz): δ=0.9 (t, 3H), 1.3 (m,3H), 1.5 (m, 2H), 1.7 (m, 1H), 1.8 (m, 4H), 2.6 (m, 1H), 4.3 (m, 1H)ppm.

EXAMPLE 29A 6-(1-Aminopropyl)-3-(4-bromophenyl)-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 23A, 5.0 g (14.2 mmol)N-{1-[3-(4-bromo-phenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamideand proportionate amounts of the other reagents are used.

Yield: 3.4 g (77%) 1H-NMR (300 MHz, CD₃OD): δ=1.02 (t, 3 H), 1.87-2.22(m, 5 H, s at 1.96), 4.42-4.53 (t, 1 H), 7.63 (d, 2 H), 8.09 (d, 2 H)ppm.

EXAMPLE 30A 6-(1-Aminopropyl)-3-cyclopropyl-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 23A, 4.90 g (20.7 mmol)N-[1-(3-cyclo-propyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]acetamideand proportionate amounts of the other reagents are used.

Yield: 1.6 g (40%) LC/MS (method A): retention time 0.36 min., m/z 195[M+H]⁺

EXAMPLE 31A 6-(1-Aminopropyl)-3-tert-butyl-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 23A, 1.77 g (4.42 mmol)N-[1-(3-tert-butyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]acetamideand proportionate amounts of the other reagents are used.

Yield: 850 mg (91%) ¹H-NMR (400 MHz, CD₃OD): δ=0.99 (t, 3H), 1.34 (s,9H), 1.82-2.12 (m, 2H), 4.34 (t, 1H) ppm.

EXAMPLE 32A 6-(1-Aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 23A, 1.65 g (6.24 mmol)N-[1-(3-cyclo-pentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]acetamideand proportionate amounts of the other reagents are used.

Yield: 900 mg (65%) ¹H-NMR (300 MHz, CD₃OD): δ=0.99 (t, 3H), 1.64-2.11(m, 10H), 3.03 (quin., 1H), 4.30 (t, 1H) ppm.

EXAMPLE 33A 6-(1-Aminopropyl)-3-(3-nitrophenyl)-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 23A, 13.5 g (42.5 mmol)N-{1-[3-(3-nitro-phenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamideand proportionate amounts of the other reagents are used.

Yield: 6.2 g (41%) LC/MS (method A): retention time 0.497 min., m/z 276[M+H]⁺

EXAMPLE 34A 6-(1-Aminopropyl)-3-phenyl-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 23A, 10.00 g (36.7 mmol) ofExample 21A and proportionate amounts of the other reagents are used.

Yield: 6.7 g (77%) ¹H-NMR (DMSO-d₆, 200 MHz): δ=0.9 (t, 3H), 1.9 (m,2H), 4.1 (m, 1H), 4.3 (dd, 1H), 7.4 (m, 3H), 8.2 (m, 2H), 8.3 (bs, 2H)ppm.

EXAMPLE 35A 6-(1-Aminopropyl)-3-(1-naphthyl)-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 23A, 700 mg (2.17 mmol) ofExample 22A and proportionate amounts of the other reagents are used.

Yield: 557 mg (91%) ¹H-NMR (DMSO-d₆, 300 MHz): δ=0.9 (t, 3H), 1.8-2.2(m, 2H), 4.4 (d/d, 1H), 7.4-8.7 (m, 10H) ppm.

EXAMPLE 36AN-{1-[3-(3-Bromophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}-4-tert-butyl-cyclohexanecarboxamide

500 mg (1.62 mmol, 1 equiv.) of Example 23A are suspended in 40 mldichloro-methane, 0.48 ml (3.44 mmol, 2 equiv.) triethylamine and 328 mg(1.62 mmol) 4-tert-butylcyclohexanecarbonyl chloride are added. Thereaction mixture is stirred at room temperature until completion ofreaction (1-2 hours). The reaction mixture is added to the same volumeof IN hydrochloric acid, the organic phase is washed with 1Nhydrochloric acid and brine, dried over sodium sulfate and evaporated todryness. The product is used without further purification or purified bychromatography (flash or column chromatography or preparative HPLC).

LC/MS (A): MS (ESI): 475, 477 (M+H⁺), retention time 3.17, 3.20 min.

EXAMPLE 37A4-tert-Butyl-N-[1-(3-cyclopropyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclo-hexanecarboxamide

In analogy to the procedure for Example 36A, 250 mg (1.29 mmol)6-(1-amino-propyl)-3-cyclopropyl-1,2,4-triazin-5(4H)-one, 260 mg (1.29mmol) 4-tert-butyl-cyclohexanecarbonyl chloride and proportionateamounts of the other reagents are used. The crude product is used in thenext step without further purification.

Yield: 464 mg crude product

EXAMPLE 38A4-tert-Butyl-N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclo-hexanecarboxamide

In analogy to the procedure for Example 36A, 200 mg (0.90 mmol)6-(1-amino-propyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 180 mg (0.90mmol) 4-tert-butyl-cyclohexanecarbonyl chloride and proportionateamounts of the other reagents are used. The crude product is used in thenext step without further purification.

Yield: 350 mg crude product

EXAMPLE 39A4-tert-Butyl-N-[1-(3-tert-butyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclo-hexanecarboxamide

In analogy to the procedure for Example 36A, 210 mg (1.00 mmol)6-(1-amino-propyl)-3-tert-butyl-1,2,4-triazin-5(4H)-one, 200 mg (1.00mmol) 4-tert-butylcyclo-hexanecarbonyl chloride and proportionateamounts of the other reagents are used. The crude product is used in thenext step without further purification.

Yield: 377 mg crude product

EXAMPLE 40A4-tert-Butyl-N-[1-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclo-hexanecarboxamide

In analogy to the procedure for Example 36A, 100 mg (0.43 mmol) ofExample 34A, 100 mg (0.48 mmol) 4-tert-butylcyclohexanecarbonyl chlorideand proportionate amounts of the other reagents are used. A mixture ofisomers is obtained.

Yield: 150 mg (87%) LC/MS (A): MS (ESI): 397 (M+H⁺), retention time 4.14min.

EXAMPLE 41Acis-4-tert-Butyl-N-{1-[3-(1-naphthyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}-cyclohexanecarboxamide

To a solution of 252 mg (1.37 mmol)cis-4-tert-butylcyclohexanecarboxylic acid and 185 mg (1.37 mmol)1-hydroxy-1H-benzotriazol in 9 ml dichloromethane and 1 ml DMF was addedat 0° C. first 0.23 ml N-ethyldiisopropylamine and then 300 mg (0.91mmol) of Example 35A. After 10 minutes the solution was allowed to warmup to room temperature and stirred over night. The solution was dilutedwith dichloromethane and washed twice with 1N HCl solution and then with5% sodium bicarbonate solution. The organic phase was dried over sodiumsulfate, filtered and evaporated to dryness. The residue was purified bypreparative HPLC.

Yield: 215 mg (53%) ¹H-NMR (DMSO-d₆, 200 MHz): δ=0.8 (s, 9H), 1.0 (t,3H), 1,2-2.2 (m, 12H), 5.0 (m, 1H), 7.5-8.3 (m, 8H), 14.1 (br. s, 1H)ppm.

EXAMPLE 42A cis-4-tert-Butylcyclohexanecarboxylic acid

A preparative HPLC separation of cis- andtrans-4-tert-butylcyclohexanecarboxylic acid was carried out under thefollowing conditions: Feed: 10 g isomeric mixture of cis- andtrans-4-tert-butyl- cyclo-hexanecarboxylic acid dissolved in 500 ml iso-hexane (80%)/tert-butylmethylether (20%) Column: 330 × 100 mm; SelfPacking Device NW 100; Merck Stationary phase: LiChrospher Si 60, 12 μm,Merck Mobile phase: iso-hexane/tert-butylmethylether (4/1 v/v) + 0.25vol-% acetic acid Flow: 150 ml/min Injection 70 ml (= 1.4 g compound)volume: Wave length: 210 nm Temperature: 25° C.

The sample run on this column was repeatedly injected every 30 minutes.The cis-isomer is the first eluting compound.

cis-isomer: mp: 118° C. ¹H-NMR (300 MHz, DMSO): δ=0.9 (t, 3 H), 1.0 (m,3 H), 1.4 (m, 2 H), 1.6 (m, 1 H), 2.1 (m, 2 H), 2.5 (m, 1 H), 12.0 (s, 1H) ppm. trans-isomer: mp: 172° C. ¹H-NMR (300 MHz, DMSO): δ=0.9 (t, 3H), 1.0 (m, 3 H), 1.3 (m, 2 H), 1.7 (m, 1 H), 1.9(m,2H),2.1 (m, 1 H),11.9(s, 1 H) ppm.

EXAMPLE 43A cis-4-tert-Butylcyclohexanecarbonyl chloride

2.0 g (10.85 mmol) cis-4-tert-Butylcyclohexanecarboxylic acid (Example42A) are dissolved in 50 ml dichloromethane, 1.65 g (13.02 mmol)ethanedioyl dichloride are added and the solution is stirred at roomtemperature for one hour. The mixture is then stirred at reflux for twohours and, after cooling down to room temperature, evaporated to drynessin vacuo. The residue is then dissolved in toluene two times and againevaporated to dryness in vacuo. The residue is used in the next stepwithout further purification.

EXAMPLE 44A 4-Nitrobenzenecarboximidamide hydrochloride

In analogy to the procedure for Example 3A, 10.0 g (67.5 mmol)4-nitrobenzonitrile and proportionate amounts of the other reagents areused.

Yield: 12.64 g (93%) ¹H-NMR (DMSO-d₆, 200 MHz): δ=8.1 (m, 2H), 8.4 (m,2H) ppm.

EXAMPLE 45A 3-Cyanobenzenecarboximidamide hydrochloride

In analogy to the procedure for Example 3A, 20.0 g (125.9 mmol)3-cyanobenzoic acid and proportionate amounts of the other reagents areused.

Yield: 4.27 g (17%) ¹H-NMR (DMSO-d₆, 300 MHz): δ=7.8 (m, 1H), 8.1 (m,1H), 8.2 (m, 1H), 8.3 (m, 1H), 9.4 (br. s, 4H) ppm.

EXAMPLE 46AN-{1-[3-(4-Methylphenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 10A, 3.0 g (17.6 mmol)4-methyl-benzenecarboximidamide hydrochloride and proportionate amountsof the other reagents are used.

Yield: 2.74 g (54%) ¹H-NMR (DMSO-d₆, 400 MHz): δ=0.9 (t, 3H), 1.6 (m,1H), 1.9 (m, 1H; s, 3H), 2.4 (s, 3H), 4.9 (m, 1H), 7.4 (m, 2H), 7.9 (m,2H), 14.0 (s, 1H) ppm.

EXAMPLE 47AN-{1-[3-(4-Nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 10A, 7.29 g (36.16 mmol) ofExample 44A and proportionate amounts of the other reagents are used.

Yield: 3.35 g (29%) ¹H-NMR (DMSO-d₆, 400 MHz): δ=0.9 (t, 3H), 1.6 (m,1H), 1.9 (m, 1H; s, 3H), 5.0 (m, 1H), 8.1 (d, 1H), 8.3 (m, 2H), 8.4 (m,2H) ppm.

EXAMPLE 48AN-{1-[3-(3-Cyanophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 10A, 4.27 g (23.5 mmol) ofExample 45A and proportionate amounts of the other reagents are used.

Yield: 2.41 g (34%) ¹H-NMR (DMSO-d6, 300 MHz): δ=0.9 (t, 3H), 1.6 (m,1H), 1.9 (m, 1H; s, 3H), 4.9 (m, 1H), 7.8 (m, 1H), 8.1 (m, 2H), 8.3 (m,1H), 8.4 (m, 1H), 14.2 (br.s, 1H) ppm.

EXAMPLE 49A 6-(1-Aminopropyl)-3-(4-methylphenyl)-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 23A, 2.74 g (9.57 mmol) ofExample 46A and proportionate amounts of the other reagents are used.The product is used in the next step without further purification.

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.9 (t, 3H), 1.8 (m, 1H), 1.9 (m, 1H), 2.3(s, 3H), 4.1 (d/d, 1H), 7.2 (m, 2H), 8.1 (m, 2H) ppm.

EXAMPLE 50A 6-(1-Aminopropyl)-3-(4-nitrophenyl)-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 23A, 3.33 g (10.51 mmol) ofExample 47A and proportionate amounts of the other reagents are used.

Yield: 1.29 g (45%) LC/MS (A): MS (ESI): 276 (M+H⁺), retention time 0.49min.

EXAMPLE 51A3-[6-(1-Aminopropyl)-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl]benzonitrile

In analogy to the procedure for Example 23A, 2.41 g (8.11 mmol) ofExample 48A and proportionate amounts of the other reagents are used.

Yield: 1.1 g(53%) LC/MS (A): MS (ESI): 256 (M+H⁺), retention time 1.27min.

EXAMPLE 52A4-tert-Butyl-N-{1-[3-(4-methylphenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]-propyl}cyclohexanecarboxamide

In analogy to the procedure for Example 37A, 800 mg (3.27 mmol) ofExample 49A, 730 mg (3.60 mmol) 4-tert-butylcyclohexanecarbonyl chlorideand proportionate amounts of the other reagents are used. The product isused in the next step without further purification.

LC/MS (A): MS (ESI): 411 (M+H⁺), retention time 3.09 min.

EXAMPLE 53Acis-7-(4-tert-Butylcyclohexyl)-4-chloro-5-ethyl-2-(4-nitrophenyl)imidazo[5,1-f]-[1,2,4]triazine

500 mg (1.82 mmol) of Example 50A are suspended in 20 ml dichloroethane,and 276 mg (2.72 mmol) triethylamine and 552 mg (2.72 mmol)cis-4-tert-butyl-cyclo-hexanecarbonyl chloride are added. The mixture isstirred at room temperature for one hour, then 279 mg (1.82 mmol)phosphoroxychloride are added. The mixture is stirred at reflux for 3hours. After cooling down to room temperature, ethyl acetate andsaturated NaHCO₃ (aq) are added. The organic phase is washed withsaturated NaHCO₃ (aq), water and brine, dried over sodium sulfate andevaporated to dryness in vacuo. The product is purified bychromatography.

Yield: 127 mg (16%) cis-product MS (ESI): 442, 444 (M+H⁺).

EXAMPLE 54Acis-4-tert-Butyl-N-[1-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclo-hexanecarboxamide

1.3 g (5.65 mmol) of Example 34A are suspended in 50 ml1,2-dichloroethane, 0.94 ml (6.78 mmol) triethylamine and 1.26 g (6.21mmol) cis-4-tert-butyl-cyclo-hexanecarbonyl (Example 43 A) chloride areadded. The reaction mixture is stirred at room temperature overnight.The reaction mixture is diluted with dichloromethane, washed withsaturated sodium bicarbonate, the organic phase is dried over magnesiumsulfate, filtered and evaporated to dryness.

Yield: 2.2 g (98.3%) LC/MS: MS (ESI): 397 (M+H⁺), retention time 4.14min.

Preparation Examples EXAMPLE 12-(3-Bromophenyl)-7-(4-tert-butylcyclohexyl)-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

770 mg (1.62 mmol, 1 equiv.) of Example 36A are suspended in 70 mldichloro-ethane, and 373 mg (2.45 mmol, 1.5 equiv.) phosphoroxychlorideare added. The mixture is stirred at reflux for 3 hours. Then another373 mg of phosphoric trichloride are added, and stirring at reflux iscontinued over night. After cooling down to room temperature, ethylacetate and saturated NaHCO₃ (aq) are added. The organic phase is washedwith saturated NaHCO₃ (aq), water and brine, dried over sodium sulfateand evaporated to dryness in vacuo. The product is purified and theisomers are separated by chromatography (flash or column chromatographyor preparative HPLC).

Yield: 156 mg (21%) cis-isomer ¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H),1.1 (m, 2H), 1.2 (t, 3H), 1.5 (m, 2H), 1.7 (m, 2H), 2.2 (m, 2H), 2.9 (q,2H), 3.5 (m, 1H), 7.5 (m, 1H), 7.8 (m, 1H), 8.0 (m, 1H), 8.1 (m, 1H),11.8 (s, 1H) ppm.

EXAMPLE 27-(4-tert-Butylcyclohexyl)-2-cyclopropyl-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

In analogy to the procedure for Example 1, 464 mg (1.29 mmol) crude4-tert-butyl-N-[1-(3-cyclopropyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclohexane-carboxamide,200 mg (1.29 mmol) phosphoric trichloride are stirred at reflux for 3hours, and proportionate amounts of the solvents are used. The resultingmixture is separated into the isomers via silica gel chromatography witheluent cyclohexane/ethylacetate 5/1, 2/1.

Yield: 20 mg (4.5%) cis-isomer ¹H-NMR (200 MHz, DMSO-d₆): δ=0.82 (s,9H), 0.93-1.11 (m, 5H), 1.18 (t, 3 H), 1.44-2.18 (m, 9 H), 2.83 (q, 2H), 3.33 (m, 1 H), 11.62 (s, 1H, NH) ppm.

EXAMPLES 3 AND 42-tert-Butyl-7-(4-tert-butylcyclohexyl)-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

In analogy to the procedure for Example 1, 377 mg (1.00 mmol) crude4-tert-butyl-N-[1-(3-tert-butyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclohexanecarb-oxamide,184 mg (1.20 mmol) phosphoric trichloride are stirred at reflux for 3hours, proportionate amounts of the solvents are used. The resultingmixture is separated into the pure cis- and trans-isomers via silica gelchromatography with eluent cyclo-hexane/ethylacetate 10/1, 5/1.

Yield: 22 mg (6.13%) cis-isomer (Example 3) ¹H-NMR (200 MHz, DMSO-d₆):δ=0.82 (s, 9 H), 0.95-1.12 (m, 1 H), 1.18 (t, 3 H), 1.28 (s, 9 H),1.46-1.72 (m, 6 H), 2.09-2.23 (m, 2 H), 2.85 (q, 2 H), 3.43 (m, 1 H),11.22 (s, 1 H, NH) ppm.

Yield: 60 mg (17%) trans-isomer (Example 4) ¹H-NMR (200 MHz, DMSO-d₆):δ=0.87 (s, 9 H), 0.93-1.12 (m, 3 H), 1.18 (t, 3 H), 1.03 (s, 9 H),1.48-2.07 (m, 6 H), 2.83 (q, 2 H), 2.98 (m, 1 H) ppm.

EXAMPLES 5 AND 67-(4-tert-Butylcyclohexyl)-2-cyclopentyl-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

In analogy to the procedure for Example 1, 350 mg (0.90 mmol) crude4-tert-butyl-N-[1-(3-cyclopentyl-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl)propyl]cyclohexane-carboxamide,140 mg (0.90 mmol) phosphoric trichloride are stirred at reflux for 3hours, proportionate amounts of the solvents are used. The isomers areseparated by chromatography.

Yield: 21 mg (6.3%) cis-isomer (Example 5) ¹H-NMR (200 MHz, DMSO-d₆):δ=0.82 (s, 9 H), 0.98-1.12 (m, 1 H), 1.18 (t, 3 H), 1.44-2.01 (m, 14 H),2.05-2.20 (m, 2 H), 2.77-2.98 (m, 3 H), 3.40 (m, 1 H) ppm.

Yield: 31 mg (17%) trans-isomer (Example 6) ¹H-NMR (200 MHz, DMSO-d₆):δ=0.86 (s, 9H), 1.03-1.26 (m, 5 H, t at 1.17), 1.45-2.18 (m, 14 H),2.74-3.03 (m, 3H) ppm.

EXAMPLES 7 AND 87-(4-tert-Butylcyclohexyl)-5-ethyl-2-phenylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

Method a)

In analogy to the procedure for Example 1, 150 mg (0.39 mmol) of Example40A, 250 mg (1.61 mmol) phosphoric trichloride are stirred at reflux for3 hours, proportionate amounts of the solvents are used. The isomers areseparated by chromatography.

Yield: 26 mg (18%) trans-isomer (Example 7) ¹H-NMR (300 MHz, DMSO):δ=0.87 (s, 9 H), 1.03-1.28 (m, 3 H), 1.23 (t, 3 H), 1.52-1.72 (m, 2 H),1.78-1.93 (m, 2 H), 1.99-2.10 (m, 2 H), 2.90 (q, 2 H), 3.07-3.21 (m, 1H), 7.51-7.67 (m, 3 H), 7.93-8.02 (m, 2 H), 11.95 (s, 1 H) ppm.

Yield: 11 mg (8%) cis-isomer (Example 8) ¹H-NMR (300 MHz, DMSO): δ=0.83(s, 9 H), 1.00-1.16 (m, 1 H), 1.22 (t, 3 H), 1.44-1.79 (m, 6 H),2.11-2.23 (m, 2 H), 2.90 (q, 2 H), 3.49-3.59 (m, 1 H), 7.47-7.60 (m, 3H), 7.91-7.98 (m, 2 H) ppm.

Method b) for the Preparation of Example 8

7-(cis-4-tert-Butylcyclohexyl)-5-ethyl-2-phenylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

2.2 g (5.55 mmol, 1 equiv.) of Example 54A are suspended in 50 mldichloroethane, and 3.62 g (23.2 mmol, 4 equiv.) phosphoroxychloride areadded. The mixture is stirred at reflux for 4 hours. After cooling downto room temperature, dichloro-methane is added and the organic phase isquenched with water, washed with water, dried over magnesium sulfate,and evaporated to dryness in vacuo. The solid residue is washed withdiethyl ether, filtered and dried.

Yield: 1.02 g (49%) ¹H-NMR identical with above (see method a).

Method c) for the Preparation of Example 8

20.45 g (0.09 mol) 6-(1-Aminopropyl)-3-phenyl-1,2,4-triazin-5(4H)-one(Example 34A) are dissolved in dichloroethane, 502 g (5.08 mol)triethylamine and 19.8 g (0.10 mol) cis-4-tert-butylcyclohexanecarbonylchloride are added. The solution is stirred at reflux for three hours,then 20.42 g (0.13 mol) phosphoroxychloride are added. The solution isstirred at reflux for another 4 hours and, after cooling down to roomtemperature, water, sodium hydroxide and then dichloromethane are added.The organic phase is evaporated to dryness in vacuo, and the residuetriturated with diethylether and filtrated. The solid is dissolved inmethanol (75%)/dichloro-methane (25%), the dichloromethane is evaporatedin vacuo, and the crystallized product is filtered and dried.

Yield: 17.8g (52%) ¹H-NMR identical with above (see method a).

EXAMPLE 97-(cis-4-tert-Butylcyclohexyl)-5-ethyl-2-(1-naphthyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one

A solution of 200 mg (0.45 mmol) of Example 41A and 104 mg (0.67 mmol)phosphoric trichloride in 10 ml 1,2-dichloroethane is stirred at refluxfor 4 hours. After work-up analogously to the procedure given forExample 1, the product was obtained as a solid.

Yield: 172 mg (89%) Melting point: 203° C. ¹H-NMR (DMSO-d₆, 200 MHz):δ=11.9 (s, 1H), 8.3-7.5 (m, 7H), 3.5 (m, 1H), 2.9 (q, J=7.5 Hz, 2H), 2.1(m, 2H), 1.7-1.5 (m, 6H), 1.3 (t, J=7.5 Hz, 3H), 1.0 (m, 1H), 0.8 (s,9H) ppm.

EXAMPLE 107-(cis-4-tert-Butylcyclohexyl)-5-ethyl-2-(4-methylphenyl)imidazo[5,1-f][1,2,4]-triazin-4(3H)-one

In analogy to the procedure for Example 1, 1750 mg (4.26 mmol) ofExample 52A, 980 mg (6.39 mmol) phosphoric trichloride are stirred atreflux over night, proportionate amounts of the solvents are used.

Yield: 40 mg (2%) ¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (t, 9H), 1.1 (m, 1H),1.2 (t, 3H), 1.6 (m, 6H), 2.2 (m, 2H), 2.4 (s, 3H), 2.9 (q, 2H), 3.5 (m,1H), 7.4 (m, 2H), 7.9 (m, 2H), 11.7 (s, 1 H) ppm.

EXAMPLE 117-(cis-4-tert-Butylcyclohexyl)-5-ethyl-2-(4-nitrophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one

598 mg (1.35 mmol) of Example 53A are suspended in methanol, and 10 mlsodium hydroxide (10% in water) are added. The mixture is stirred atreflux over night. After cooling down to room temperature, the methanolis evaporated in vacuo, the residue dissolved in ethyl acetate, theorganic phase washed with water and brine, dried over sodium sulfate andevaporated to dryness in vacuo.

Yield: 580 mg (quant.) ¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m,1H), 1.2 (t, 3H), 1.5-1.7 (m, 6H), 2.2 (m, 2H), 2.9 (q, 2H), 3.6 (m,1H), 8.2 (m, 2H), 8.4 (m, 2H), 12.1 (s, 1H) ppm.

EXAMPLES 12 and 137-(4-tert-Butylcyclohexyl)-5-ethyl-2-(3-fluorophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one

500 mg (2.01 mmol) of Example 25A are suspended in 20 ml dichloroethane,and 306 mg (3.02 mmol) triethylamine and 408 mg (2.01 mmol)4-tert-butyl-cyclo-hexanecarbonyl chloride are added. The mixture isstirred at room temperature for one hour, then 463 mg (3.02 mmol)phosphoroxychloride are added. The mixture is stirred at reflux for 3hours. After cooling down to room temperature, ethyl acetate andsaturated NaHCO₃ (aq) are added. The organic phase is washed withsaturated NaHCO₃ (aq), water and brine, dried over sodium sulfate andevaporated to dryness in vacuo. The product is purified bychromatography.

Yield: 33 mg (4%) cis-product (Example 12) ¹H-NMR (DMSO-d₆, 200 MHz):δ=0.8 (s, 9H), 1.0 (m, 1H), 1.2 (t, 3H), 1.5-1.7 (m, 6H), 2.2 (m, 2H),2.9 (q, 2H), 3.6 (m, 1H), 7.5 (m, 1H), 7.6 (m, 1H), 7.8 (m, 2H), 12.0(br.s, 1H) ppm. Yield: 29 mg (4%) trans-product (Example 13) ¹H-NMR(DMSO-d₆, 200 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H), 1.6 (m,4H), 1.9 (m, 2H), 2.0 (m, 2H), 2.9 (q, 2H), 3.1 (m, 1H), 7.5 (m, 1H),7.6 (m, 1H), 7.8 (m, 2H) ppm.

EXAMPLE 14cis-3-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl]benzonitrile

In analogy to the procedure for Examples 12 and 13, 1.09 g (4.27 mmol)of Example 51A, 0.86 g (4.27 mmol) cis-4-tert-butylcyclohexanecarbonylchloride and proportionate amounts of the other reagents are used.

Yield: 0.70 g (41%) ¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m,1H), 1.2 (t, 3H), 1.5-1.7 (m, 6H), 2.2 (m, 2H), 2.9 (q, 2H), 3.6 (m,1H), 7.7 (m, 1H), 8.0 (m, 1H), 8.3 (m, 1H), 8.4 (m, 1H), 11.9 (s, 1H)ppm.

1) (cancelled)
 2. (cancelled)
 3. (cancelled)
 4. (cancelled) 5.(cancelled)
 6. (cancelled)
 7. (cancelled)
 8. (cancelled)
 9. (cancelled)10. A method of preventing chronic obstructive pulmonary disease,comprising administering to a mammal an effective amount of a compoundof formula (I),

in which R¹ denotes (C₆-C₁₀)-aryl, which is optionally substituted byidentical or different residues selected from the group consisting ofhalogen (C₁-C₄)-alkyl, trifluoromethyl, cyano, nitro andtrifluoromethoxy, or denotes (C₁-₈)-alkyl, which is optionallysubstituted by 3- to 10-membered carbocyclyl, or denotes 3- to10-membered carbocyclyl, which is optionally substituted by identical ordifferent (C₁-C₄)-alkyl residues, and R² denotes4-tert-butyl-cyclohex-1-yl, or a salt, hydrate or solvate thereof. 11.The method of claim 10, wherein R¹ denotes napththyl, or denotes phenyl,which is optionally substituted by identical or different halogen atoms.12. The method of claim 10, wherein R² denotescis-4-tert-butyl-cyclohex-1-yl.
 13. The method of claim 10, wherein thecompound is7-(cis-4-tert-butylcyclohexyl)-5-ethyl-2-(3-fluorophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one.
 14. The method of claim 10, wherein thecompound is7-(cis-4-tert-butylcyclohexyl)-5-ethyl-2-phenylimidazo[5,1-f][1,2,4]triazin-4(3H)-one.15. A method of preventing asthma, comprising administering to a mammalan effective amount of a compound of formula (I),

wherein R¹ denotes (C₆-C₁₀)-aryl, which is optionally substituted byidentical or different residues selected from the group consisting ofhalogen, (C₁-C₄)-alkyl, trifluoromethyl, cyano, nitro andtrifluoromethoxy, or denotes (C₁-C₈)-alkyl, which is optionallysubstituted by 3- to 10-membered carbocyclyl, or denotes 3- to10-membered carbocyclyl, which is optionally substituted by identical ordifferent (C₁-C₄)-alkyl residues, and R² denotes4-tert-butyl-cyclohex-1-yl, or a salt, hydrate or solvate thereof. 16.The method of claim 15, wherein R¹ denotes napththyl, or denotes phenyl,which is optionally substituted by identical or different halogen atoms.17. The method of claim 15, wherein R²denotescis-4-tert-butyl-cyclohex-1-yl.
 18. The method of claim 15, wherein thecompound is7-(cis-4-tert-butylcyclohexyl)-5-ethyl-2-(3-fluorophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one.
 19. The method of claim 15, wherein thecompound is7-(cis-4-tert-butylcyclohexyl)-5-ethyl-2-phenylimidazo[5,1-f][1,2,4]triazin-4(3H)-one.